Therapeutic compositions containing 17 alpha-methyl-4, 6-androstadine-17beta-ol-3-one



ilnited States Patent 3,033,752 THERAPEUTIC COMPOSITIONS CONTAINING17a.- METHYL-4,6-ANDROSTADIEN-17fi-OL-3-ONE Raymond 0. Clinton andRobert G. Christiansen, Schodack, N.Y.,' assignors to Sterling DrugInc., New York, N.Y., a corporation of Delaware No Drawing. Filed Oct.17, 1958, Ser. No. 767,766 4 Claims. (Cl. 167-74) This invention relatesto the preparation of steroid 4,6-dienes, and in particular it relatesto the preparation of 17a-lower-alkyl-17B-RO-4,6-androstadien-3-oneshav..- ing the formula R CH wherein R is a lower-alkyl group, and R isselected from the group consisting of hydrogen and acyloxy groups. Theinvention also relates to intermediates in the preparation of compoundsof Formula I, and to hormonal compositions containing the species ofFormula I wherein R is methyl (CH and R is hydrogen (H).

In the above general Formula I the group R represents a lower-alkylgroup, preferably one having from one to about nine carbon atoms whichcan be straight or branched, thus including such groups as methyl,ethyl, propy1,isopropyl, butyl, isobutyl, secondary-butyl,tertiarybutyl, pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, and thelike.

In the above general formula the group R represents a hydrogen atom oran acyl group. The acyl group is preferably one derived from ahydrocarbon carboxylic acid having from one to about nine carbon atoms,thus including acyl groups derived from lower-alkanoic acids, monocycliccycloalkanecarboxylic acids, cycloalkyl substituted lower-alkanoicacids, monocyclic aromatic acids, arylalkanoic acids, and the like. ThusR can include such groups as o y c s/ p sp bu s wy yl, yc o ne y cy lhsxy s si l, l-ohexylpropionyl, cyclopentylpropionyl, benzoyl,phenylacetyl, and the like. A particularly preferred class of acylgroups is the class of lower-alkanoyl radicals having from one to aboutnine carbon atoms.

The preparation of the compounds of Formula I is illustrated by thefollowing reaction:

A 17a-lower-alkyl-17,8-RO-4-androsten-3-one (II) is halogenated in the 6position with an N-halo compound, followed by dehydrohalogenation of theresulting 6-halo derivative (III) by heating with a base (the halogencan be chlorine or bromine, preferably bromine):

Patented May 8, 1962 R (1111 um III The starting materials of Formula IIbelong to generally known classes of compounds. They are readilyprepared from dehydroepiandrosterone; for instance, a reaction betweenthe latter and a lower-alkyl-magnesium halide or a lower-alkyl-lithium,and oxidation of the 3-hydroxy group with such agents as chromic oxideor aluminum tertiarybutoxide gives the 3-ketorN-compounds of Formula II.

If compounds wherein R is an acyl group are desired, the esterificationof the 17fl-hydroxy group can be efiected either before the halogenationand dehydrohalogenation reactions are carried out or upon the finaldiene product. It is generally preferred to carry out the esterificationon the starting material since the starting material is less susceptibleto deleterious side-reactions than the diene product. The esterificationis carried out by heating the l7B-hydroxy compound with the appropriateacid, acid anhydride or acid halide, usually in the presence of anorganic basic medium such as pyridine.

In the halogenation step the N-halo compound can be any such compoundwhich will halogenate an olefinic compound in the allyl position. Thepreferred halogenating agents are N-bromoamides or N-b'romoimides, suchas N bromosuccinimide, N bromoacetamide, N bromophthalimide,N-bromohydantoin, and the like. A compound of Formula II is heated withat least a molar equivalent amount of the N-bromo compound in an organicmedium inert under the conditions of the reaction, such as chloroform,carbon tetrachloride, petroleum ether, and the like. The reaction ispreferably carried out at a temperature between about 50 and 120 C.

The dehydrohalogenation step is efiected by heating the 6-haloderivative (III) with a base or acid-aceptor capable of splitting outthe elements of hydrogen halide from secondary halides. Such basesinclude alkali metal hydroxides and alkoxides, and organic amines. Ifalkali metal hydroxides or alkoxides are used, the reaction is carriedout in an inert medium, aqueous or non-aqueous. A preferred class ofdehydrohalogenating agents are relatively high-boiling, liquidtertiary-amines, such as the alkylated pyridines, e.g., picolines,lutidines, collidines; quinoline, and the like, or mixtures thereof. Inthis case the amine itself serves as the reaction medium. Thedehydrohalogenation with a tertiary-amine takes place at a temperaturebetween about and 250 C., and is m0st conveniently carried out at theboiling point of the amine. It is not necessary to purify the 6-halocompound prior to dehydrohalogenation.

The following examples will illustrate the invention more fully withoutlimiting the same thereto.

EXAMPLE 1 (a) G-bromo-17ot-methyl-4-androsten-1713-01-3-one (III; X isBr, R is CH R is H):

l7a-rnethyl-4-androsten-l7fleol-3-one (9.06 g., 0.0300 mole) wasdissolved in 300 ml. of carbon tetrachloride, and 50 ml. of the carbontetrachloride was distilled off to insure dryness. The solution wascooled somewhat, 5.61 g. (0.0315 mole) of N-bromosuccinimide wasadded,and the mixture was refluxed for forty-five minutes. The reactionmixture was filtered while hot, the succinirnide on the filter waswashed with 100 ml. of hot chloroform, and the combined filtrate andwashings were concentrated to dryness in vacuo. Some n-hexane was addedto the residue and then concentrated to dryness in vacuo to remove anyresidual carbon tetrachloride. The residue was triturated with n-hexane,and the solid product was collected by filtration and recrystallizedfrom 700 ml. of ether. A first crop of product was obtained amounting to1.63 g., M.P. 135-136 C. Additional crops of product were obtained byconcentrating the mother liquors, giving an additional 7.63 g. of6-bromo-17a-methyl-4-androsten-17B-ol-3-one, M.P. 11Z1M C. The firstcrop was analyzed with the following results.

Analysis.-Calcd. for C H BrO C, 62.99; H, 7.67; Br. 20.96. Found: C,63.18; H, 7.53; Br, 21.78.

By substitution in the foregoing preparation of the 170:-methyl-4-androsten-l75-ol-3-one by a molar equivalent amount of17a-ethyl-4-androsten-l75-ol-3-one, l7a-propyl-4-androsten-17-ol-3-one,17 wisopropyl-4-androsten-17,8-ol-3-one,17a-butyl-4-androsten-17fi-ol-3-one,17a-isobutyl-4-androsten-l7fl-ol-3-one,17a-hexyl-4-androsten-l7,8-01-3-one,17a-nonyl-4-androsten-17,8-01-3-one,17a-methyl-17fi-formyloxy-4-androsten-3-one, 17a-methyl-l73-propionoxy-4-androsten-B-one, 17m-methyl-l7fi-caproyloxy-4-androsten3-one, 17u-methyl-l75-110mmoyloxy-4-androsten-3-one, 17a-methy1-17;3-(fi-cyclohexylpropionoxy)-4-androsten- 3-one, or17e-methyl-17fl-benzoyloxy-4-androsten-3one,

there can be obtained, respectively,

6-bromo-17u-ethyl-4-androsten-17fi-ol-3-one,

6-bromo-l7a-propyl-4-androsten-l7B-ol-3-one,6-bromo-17a-isopropy1-4-androsten-17,8-01-3-one,6-bromo-17a-butyl-4-androsten-1713-ol-3-one,6-bromol7a-isobutyl-4-androsten-17;3-ol-3-one,6-bI'O1TlO-17CC-h6XYl-4-3Ildl'08t6fl-17fl-O1-3-OHB6-bromo-17a-nonyl-4-androsten-l7,3-ol-3-one,6-bromo-17a-methyl-17B-formyloxy-4-androsten-3-one,6-bromo-l7a-methyl-175-propionoxy-4-androsten-3-one,6-bromo-l7a-methyl-l7 8-caproyloxy-4-androsten-3-one,6-bromo-l7m-methyl-17fl-nonanoyloxy-4-androsten-3-one, 6-bromo-l7a-methyl- 1 75-( ,B-cyclohexylpropionoxy) -4- androsten-3-one, or6-bromo-17a-methyl-l7fl-benzoyloxy-4-androsten-3-one.

(b) 17u-methyl-4,6-androstadien-l7B-ol-3-one (I; R is CH R is H):

A mixture of 6.85 g. of 6-bromo-17a-methyl-4androsten-17B-ol-3-one and50 ml. of freshly distilled gamma-collidine was refluxed for forty-fiveminutes. The reaction mixture was cooled to room temperature and pouredinto 400 ml. of water containing cracked ice and 25 ml. of concentratedsulfuric acid. The yellow-orange solid which formed was collected byfiltration, washed with water and dried at 50 C., giving 4.92 g., M.P.179- 183 C. (dec.). 400 m1. of benzene and chromatographed on a columnof 200 g. of aluminum oxide. The product was eluted with sixteen 400 ml.portions of benzene, five 400 ml. portions of 20% other in benzene andfive 800 ml. portions of ether, which were evaporated to givecrystalline fractions melting about 190l96 C. These fractions werecombined and recrystallized first'from' acetone and then from ethylacetate, giving a sample of l7u-methyl-4,6-androstadien-l7fl-ol-3-one,M.P. 196-1975 C. (corn), E =25991 at 283 m... (in ethanol),

11% in chloroform).

Analysis.Calcd. for ,11 ,0 1 (2, 19.95; H, 9.39. Found: C, 79.92; H,9.49.

The latter material Was dissolved in By substitution in the foregoingpreparation of the 6- bromo-l7a-methyl-4-androsten-17fi-ol-3-one by amolar equivalent amount of 6-bromo-17a-ethyl-4-androsten-17fl-ol-3-one,6-bromo-17u-propyl-4-androsten-17/3-ol-3-one,6-bromo-l7ot-isopropyl-4-androsten-17fi-ol-3-one,6-bromo-l7a-butyl-4-androsten-17fi-ol-3-one,6-bromo-17a-isobutyl-4-androsten-17,8-ol-3-one,6-bromo-l7a-hexyl-4-androsten-1 7;8-ol-3-one,6-bromo-17a-nonyl-4-androsten-17,6-ol-3-one, 6-bromo-l 7a-methy1-17,8-formyloxy-4-androsten-3-one,6-bromo-17ot-methy1-17/3-propionoxy-4-androsten-3-one,6-bromo-l7a-methyl-l7B-caproyloxy-4-androsten-3-one,6-bromo-17m-methyl-17fi-nonanoyloxy-4-androsten-3-one, 6-bromo-l7u-methyl- 17 ,8- B- cyclohexylpropionoxy) -4- androsten-3-one, or6-bromo-17u-methyl-17B-benzoyloxy-4-androsten-3-one,

there can be obtained, respectively,

17a-ethyl-4,6-androstadien-17B-ol-3-one,17a-propyl-4,6-androstadien-l7/3-ol-3-one,17a-isopropyl-4,6-androstadienl7fi-ol-3-one,l7a-butyl-4,6-androstadien-17p-ol-3-one,l7a-isobutyl-4,6-androstadien-l7B-ol-3-one,l7a-hexyl-4,6-androstadien-17,3-ol-3-one,17a-nonyl-4-androstadien-17;3-ol-3-one,17a-methyl-17fi-formyloxy-4,6-androstadien-3-one,17u-methyl-1718-propionoxy-4,6-androstadien-3-one, 17a-methyll78-caproyloxy-4,6-androstadien-3-one,l7u-methyl-17f3-nonanoyloxy-4,6-androstadien-3-one, 17a-methyl-175-(fl-cyclohexylpropionoxy)-4,6-

androstadien-B-one, or17a-methyl-17/8-benzoyloxy-4,6-androstadien-3-one.

EXAMPLE 2 l7c -methyl-4,6-androstadien-l'7fi-ol-3-one (withoutpurification of the intermediate 6-bromo derivative):

17a-methyl-4-androsten-17fi-ol-3-one (60.49 g., 0.200 mole) and 2500 ml.of carbon tetrachloride were mixed and about 25 ml. of carbontetrachloride was distilled off to insure dryness. After coolingsomewhat, 71.2 g. (0.400 mole) of N-bromo-succinirnide was added, andthe mixture was refluxed for five hours in the dark (covered with ablack cloth). The resulting orange solution, containing suspended solid,was cooled to about 35 C., filtered, and the insoluble succinimide waswashed with two 300 ml. portions of warm carbon tetrachloride. Thecombined filtrate and washings were evaporated to dryness in vacuo usinga water bath held below 40 C. To the solid residue of6-bromo-l7a-methyl-4-androsten-1713- ol-3-one was added 300 ml. ofn-hexane and the mixture was again evaporated in vacuo. The residue wasthen mixed with 400 ml. of redistilled gamma-collidine (coal tarcollidine, B.P. 161-174 C.) and distilled until the vapor temperaturereached C. The reaction mixture was then refluxed for a further twentyminutes at 160-165 C., then cooled and poured into three liters of icewater containing ml. of concentrated sulfuric acid. After mixing well,the semi-crystalline dark brown solid was collected by filtration andthoroughly washed with water. The resulting product was dried at 50 C.,dissolved in 700 ml. of boiling acetone, treated with 4 g. of activatedcharcoal for decolorizing purposes, filtered, and the filtrateevaporated to a volume of. 250 ml. for crystallization. After thoroughcooling the crystals were collected by filtration, washed with three 20ml. portions of cold acetone, and recrystallized from acetone, giving21.82 g. of material melting at 191-195 C., in the form of yellowleaflets. Concentration of the mother liquors to a volume of 75 ml.,filtration of the product and recrystallization from acetone gave anadditional 6.57 g. of material melting at 191-194 C. A finalrecrystallizadi M 5. tion of the total product from acetone gave a totalyield of 26.71 of pure 17a-methyl-4,6androstadien-170013- one, M.P.196l97.5 C. (corn).

EXAMPLE 3 17a-methyl-17B-propionoxy-4,6,androstadien-3-one (I; R is CH Ris QCCH CH A mixture of 2.10 g. (0.0070 mole) of 17a-methyl-4,6-androstadien-17fl-ol-3-one, 4.55 g. (0.035 mole) of propionic anhydrideand 25 ml. of pyridine was refluxed for six and one-half hours. Thereaction mixture was kept at room temperature for fifteen hours and thenpoured into ice water containing a small amount of sulfuric acid. Theproduct was extracted with chloroform, the chloroform extracts werewashed with saturated sodium carbonate solution and dried over anhydroussodium sulfate. The chloroform solution was concentrated to dryness andthe residue was crystallized from hexane. The solid material wascollected by filtration and proved to be some recovered startingmaterial. The hexane mother liquors upon concentration gave an oilcontaining 170:- methyl-l7/8-propionoxy-4,6-androstadien-3-one. The oilwas dissolved in n-pentane containing 10% ether and chromatographed on acolumn of 150 g. of silica gel. The column was eluted successively with10% ether in n-pentane, ether in n-pentane and 25% ether in n -pentane.The last named solvent mixture brought out crystalline material, whichupon two recrystallizations from dilute methanol gave Not-methyl-173-propionoxy- 4,6-androstadien-3-one in the form of pale yellowleaflets, M.P. 7788 C.

EXAMPLE 4 17a methyl 17,3 acetoxy 4,6 androstadien 3- one (I; R is CH Ris OCCH A mixture of 10.27 g. (0.0298 mole) of17a-methyll7,8-acetoxy-4-androsten-3-one and 5.36 g. (0.0301 mole) ofN-bromo-succinimide in 300 ml. of carbon tetrachloride was refluxed forone and one-half hours. The reaction mixture was cooled to roomtemperature, and the succinirnide was removed by .filtration and washedwith carbon tetrachloride. The combined filtrate and washings wereconcentrated to dryness in vacuo at 3540 C. and then held in vacuo forone and one-half hours at room temperature to remove residual solvent.The residue containing 6-bromo-17u-methyl-l7/8-acetoxy-4-androsten-3-onewas dissolved in 40 ml. of 2,4-lutidine and 40 ml. of gamma-collidineand the solution was refluxed for one hour. The solution was cooled andpoured into ice water containing 40 ml. of concentrated sulfuric acid.The product was extracted with methylene dichloride, and the extractswere washed with dilute sulfuric acid, water, and dilute sodiumbicarbonate solution, and dried over anhydrous sodium sulfate. Themethylene dichloride solution was concentrated to dryness, the residuewas dissolved in 100 ml. of hot n-hexane, 400 ml. of n-pentane wasadded, and the solution was chromatographed on a column of 300 g. ofsilicon dioxide pre-wet with n-pentane. The remaining residue whichfailed to dissolve in the n-hexane was further extracted with n-hexane,n-pentane added, and the solution added to the column. The column waseluted successively with n-pentane, and npentane containing graduallyincreasing proportions of ether. The eluates from n-pentane containing20-30% ether upon concentration gave crystalline material, combinedweight 7.12 g., M.P. ll44 C. The latter product was dissolved in 300 ml.of boiling n-hexane, filtered while hot, and the solution concentratedto a volume of 75 ml. and cooled. The product which crystallized wascollected by filtration, washed with cold n-hexane, dried at 70 C. andrecrystallized twice from methanol, giving17a-methyl-l7p-acetoxy-4,6-androstadien-3-one in the form of pale yellowneedles, M.P. 148150 C. The analytic sample was dried for eight hours at100 C. in vacuo and had a corrected melting point 149.5-152.5 C.,

6 [a] =+45 (1% in chloroform), E =26630 at 284 me (in ethanol).

Analysis.-Calcd. for C l-1 0 C, 77.15; H, 8.83. Found: C, 77.25; H,8.91.

EXAMPLE 5- 17a. ethyl 4,6 androstadien 17,8 ol 3 one (I; R is CH CH R isH):

A mixture of 10.02 g. (0.0317 mole) of l7a-ethyl-4-androsten-17B-ol-3-one and 5.76 g. (0.0317 mole) of N- bromo-succinimidein 200 ml. of carbon tetrachloride was refluxed for forty minutes. Thereaction mixture was cooled, filtered, and the filtrate concentrated invacuo below 50 C. n-Hexane was added to the residue and evaporated at 30C. invacuo. The residue (12.5 g.) of crude 6 bromo 17a ethyl 4 androsten17B ol- 3-one and ml. of gamma-collidine was refluxed for one hour. Thereaction mixture was cooled and added to 1 liter of ice water containing50 ml. of concentrated sulfuric acid. The precipitate which formed wascollected by filtration and the filtrate extracted with ether. Theprecipitate was dissolved in the ether extracts and the solution waswashed with dilute sulfuric acid, water, and sodium carbonate solution,and dried over anhydrous sodium sulfate. The ether solution wasconcentrated to a small volume, and the crystalline material whichseparated was collected and recrystallized successively from an ethylacetate-ether mixture, a benzene-ether mixture, and ethanol, and driedat 100 C. in vacuo for six hours, giving 17a-ethyl-4,6-androstadien-17,8o1 13 one, M.P. l77.5182 C. (corn), [a] =+14.9 (1% in chloroform), E=26260 at 285 m (in 95% ethanol).

Analysis.-Calcd. for C H O C, 80.21; H, 9.62. Found: C, 80.55; H, 9.79.

Additional product was obtained from the mother liquors by concentratingthem, and chromatographing an n-pentane solution of the residue on acolumn of magnesium silicate. The column Was eluted with n-pentanecontaining gradually increasing amounts of methylene dichloride up to50%, and then with n-pentane containing gradually increasing amounts ofether. The desired product was brought out with n-pentane containing 5to 40% ether.

The compounds of Formula I possess useful hormonal activities; forexample, anabolic, myotrophic, androgenic and pituitary inhibitingproperties. Of especial advantage is 17a methyl 4,6 androstadien ol 3one, which has been found to have an anabolic activity onethird that oftestosterone propionate in effecting nitrogen retention While beingdevoid of androgenic or estrogenic activity. Surprisingly, the nexthigher homolog, 17a-ethyl- 4,6-androstadien-l75-ol-3-one has been foundto be essentially devoid of anabolic activity. 17a-methyl-4,6-androstadien-l7fi-ol-3-one has also been found to have a greateranti-catabolic effect than testosterone propionate in reversingcortisone-induced growth suppression.

The compositions of our invention are therapeutic hormonal compositionscomprising, as an essential ingredient thereof, l7ot-methyl 4,6androstadien 178-01- 3-o-ne in amount suflicient to impart to saidcomposition anabolic and anti catabolic properties devoid of anyappreciable degree of sex hormonal properties, and a therapeuticallyacceptable vehicle.

In the foregoing compositions the amount of active steroid ingredientcan vary from about 0.1 percent to about 50 percent by weight relativeto the total weight of the composition. A preferred range of steroidcontent ranges from about 1 percent to about 30 percent. The loweramounts of steroid, l-5 percent, are employed in compositions fortopical application; higher amounts, 15- 30 percent, in compositions fororal administration; and intermediate amounts, 215 percent, incompositions for parenteral administration.

The nature of the therapeutically acceptable vehicle can vary widely,depending upon the intended route of administration. If the compositionis to be administered parenterally by injection, the vehicle can be anaqueous solution of a surfactant or thickening agent in which thesteroid in finely divided form produces a stable suspension. Otheringredients may be present if desired, such as sodium chloride to makethe solution isotonic, butters to control pH, germicidal agents, and soforth. Alternatively, parenterally injectable aqueous suspensions can beprepared by poising the finely divided steroid in an aqueous solution ofa water-soluble, non-toxic, highly iodinated organic compound such as iscommonly used in urography, said solution having a density approximatelythe same as that of the suspended solid.

Non-aqueous compositions for intramuscular injection can be prepared bydissolving or suspending the steroid in a therapeutically acceptable oilsuch as peanut oil, cottonseed oil, olive oil, and the like. Othernon-aqueous solvents which can be employed are dimethylformamide,dimethylacetamide, absolute ethanol, and dodecyl alcohol.

If the composition is to be administered orally, the composition can bein tablet form with conventional solid excipients such as starch, talc,lactose, and 'the like. Alternatively, the steroid can be dissolved orsuspended in a therapeutically acceptable oil and placed in soft (Ipercent aqueous suspension for parenteral administration g.17u-Methyl-4,6-androstadien-17,8-ol-3-0ne 50.0 Polyethylene glycol 600monooleate 1.84 Phenyl mercuric acetate 0.018 sodium chloride 8.28

Pure wateradded to give total volume of 1000-ml.

Autoclaved at 121 C. for 20 minutes.

(2) percent aqueous suspension for parenteral administration g17a-methyl-4,6-androstadien-l7,6-ol-3-one 100.0 Polyethylene glycol 600monooleate 2.0 Phenyl mercuric acetate 0.0184 Sodium chloride 0.828

Pure water-added to give total volume of 1000 ml.

Tyndallized at 70 C. for one hour on three successive days.

(3) 10 percent (relative to total volume) poised aqueous suspension forparenteral administration 17a-methyl-4,G-androstadien-l7;8-ol-3-one g10.0 34.15 percent solution of sodium 3,5-diacetamido-2,4,6-triiodobenzoate in water ml 100.0

(4) 2 percent oil solution for intramuscular injection17a-methyl-4,6-androstadien-17fi-ol-3-one g 2.0 Benzyl alcohol ml 20Absolute ethanol -ml 15.0

Peanut oil (dried)adc led to give total volume of V (5) 28.6 percenttablet for oral administration Per tablet, g.

This application is a continuation-in-part of our copending applicationSerial No. 567,721, filed February 27, 1956, now abandoned.

We claim:

1. A therapeutic hormonal composition comprising, as an essentialingredient thereof, 17a-methyl-4,6-androstadien-17B-ol-3-one, and atherapeutically acceptable vehicle, wherein the essential ingredient ispresent in amount from about 0.1 percent to about 50 percent by weightrelative to the total weight of the composition.

2. A therapeutic hormonal composition for topical applicationcomprising, as an essential ingredient thereof, 17a-methy1-4,fi-androstadien-1758-01-3 -one, and a therapeuticallyacceptable ointment base, wherein the essential ingredient is present inamount from about 1 percent to about 5 percent by weight relative to thetotal weight of the composition.

3. A therapeutic hormonal composition for parenteral administrationcomprising, as an essential ingredient thereof,17a-methyl-4,6-androstadien-17B-ol-3-one, and a therapeuticallyacceptable liquid vehicle, wherein the essential ingredient is presentin amount from about 2 percent to about 15 percent by weight relative tothe total weight of the composition.

4. A therapeutic hormonal composition for oral administrationcomprising, as an essential ingredient thereof,17a-methyl-4,o-androstadien-l7fi-ol-3-one, and therapeuticallyacceptable vehicles, wherein the essential ingredient is present inamount from about 15 percent to about 30 percent by weight relative tothe total weight of the composition.

References Cited in the file of this patent UNITED STATES PATENTS2,085,474 Ruzicka June 29, 1937 2,694,079 Holysz Nov. 9, 1954 2,715,640Rails Aug. 16, 1955 2,739,974 Colton Mar. 27, 1956 2,837,464 Nobile June3, 1958

1. A THERAPEUTIC HORMONAL COMPOSITION COMPRISING, AS AN ESSENTIALLINGREDIENT THEREOF, 17 A-METHYL-4,6-ANDROSTADIEN-17 B-OL-3-ONE, AND ATHERAPEUTICALLY ACCEPTABLE VEHICLE, WHEREIN THE ESSENTIAL INGREDIENT ISPRESENT IN AMOUNT FROM ABOUT 0.1 PERCENT TO ABOUT 50 PERCENT BY WEIGHTRELATIVE TO THE TOTAL WEIGHT OF THE COMPOSITION.